T cell senescence induced by DNMT1 deletion mediates cardiac transplant tolerance via altered CDKN1A methylation

This study investigates the role of DNA methyltransferase 1 (DNMT1) in T cell senescence and heart transplant rejection using mouse models and clinical data. In the mouse heart transplantation model, DNMT1 was found to be highly expressed in graft-infiltrating T cells. Using Dnmt1^flox/floxCd4^cre/+ mice, researchers demonstrated that T cell-specific knockout of DNMT1 led to long-term graft survival by impairing effector differentiation and promoting senescence in CD4⁺ T cells rather than in CD8⁺ T cells. Whole-genome methylation sequencing and RNA sequencing revealed that DNMT1 knockout decreased methylation of the cyclin-dependent kinase inhibitor 1A (CDKN1A) promoter, upregulating CDKN1A expression. Depletion of CDKN1A^high cells reversed DNMT1-inhibitor-induced T cell senescence. Clinically, increased T cell senescence was observed in post-transplant patients and is known to increase with age. Additionally, data from the UNOS database showed lower rejection rates in older recipients (age >65). These findings suggest that DNMT1 ablation accelerates CD4⁺ T cell senescence by altering CDKN1A methylation, thereby reducing T cell function and mitigating rejection. DNMT1 may thus serve as a potential therapeutic target for heart transplant rejection.